Sleeplessness and depression are well known problems which are suffered daily by countless people. A vast compendium of reliable and effective pharmacologically active agents are known to treat these conditions. However, in view of their various side effects, they cannot be utilized without some care and thought. Where it is necessary to treat these conditions on a long term basis, care must be taken to avoid setting up dependencies, particularly where benzodiazepines are involved. It should be noted that barbiturates and other well accepted sleeping aids can lead to dependence, pose a risk of being utilized for suicidal purposes and have a plurality of side effects.
Recently, studies on the physiology of sleep have revealed various results confirming the complexity of the sleep termination and also the complex nature of the physiological and biochemical mechanisms which are responsible for the interruption of sleep and which insure the regular progression of the various phases of sleep.
Different portions of the brain take part in such mechanisms and are influenced by various transfer compounds i.e. neurotransmitters, which consist principally of amino acids.
The best known of such neuro transmitters are Noradrenalin and Dopamine (synthesized from Tyrosin and Serotonin which is synthesized from Tryptophan).
Studies have shown that low levels of particular neurotransmitters or their precursors can influence conditions of excitation which in turn often lead to psychic illnesses, for example disturbed sleep or depression. Sleep is, induced through Serotonic neurons in the so-called Raphe system in the border regions between the middle and rhombic brain. If the biosynthesis of serotonin from tryptophan is blocked in the brain, sleeplessness will occur. Lack of serotonin cannot be relieved by direct substitution since serotonin, quite apart from undesired side effects, cannot pass through the blood/brain barrier by itself. Thus, the required amino acid tryptophan must be produced in these serotonergic neurons. This synthesis takes place in two steps wherein first 5-hydroxy tryptophan is formed by the action of trytophan hydroxylase, which is then decarboxylated by aromatic aminoacid decarboxylase to yield 5-hydroxy tryptamine, that is to say serotonin.
Thus a lack of tryptophan gives rise to disturbances of sleep and depressions. Tryptophan insuffiency and its effects were therefore successfully treated by administration of free tryptophan which can indeed pass through the blood/brain barrier. Such a treatment has certain advantages vis a vis the classical antidepressants which block the inactivation of central transfer agents such as serotonin and the conventional hypnotics which unspecifically dampen the activating formatio reticolaris. The advantage of this therapy is that it is direct and free from side effects since it does not lead to dependency or addiction. It does not give rise to the risk of being a suicidal agent and furthermore gives the posibility, in cases of severe disturbance, of enabling a reduction of the required dosage of active pyschopharmaceutical agents by the administration of tryptophan (see Der Deutsche Apotheker) (The German Pharmacist) 35 #4 1-7(1983)).
The problem with the administration of tryptophan which can only pass the blood/brain barrier in its free form lies in the relatively low levels of resorption, that is to say, resorbability of the tryptophan from the gastrointestinal tract and the rather limited transportation of tryptophan through tissue membranes so that tryptophan must be administered in higher doses and with greater dosage frequency than is desirable. In order to treat cerebral disturbances it is desirable to maintain a high level of serotonin in the brain and a low level in the blood, since otherwise a high serotonin level in the blood can lead to peripheral disturbances.
Heretofore, attempts have been made to utilize the serotonin precursor 5-hydroxy tryptophan in place of serotonin or tryptophan. The problem with this approach is that 5-hydroxy tryptophan is readily changed by decarboxylase in the blood into serotonin so the concentration of serotonin in the blood rises to undesirable levels.
It has also been observed that there are certain undesirable intestinal side effects, for example, nausea and diarrhea. In order to avoid such side effects the 5-hydroxy tryptophan must be administered together with a decarboxylase blocking agent such as Benserozide (INN) that is to say N-(DL)-seryl N'-(2,3,4-trihydroxy benzyl) hydrazine or Carbidopa (INN) that is to say (-)-L-alphahydrazinyl-3,4-dihydroxy-alpha methyl hydroxycinnamic acid. These decarboxylase blockers however have the disadvantage that they also give rise to undesired and occasionally substantially bothersome side effects.
It is therefore still desirable to provide suitable materials for the therapy of cerebral disturbances in particular sleeplessness and depression. The task of the present invention therefore was to provide a new agent for the treatment of cerebral disturbances such as sleeplessness and depression which does not have the disadvantages of the known agents, which does not require the use of decarboxylase blockers, is not a toxic and has substantially no side effects, does not lead to dependence or addiction, carries no suicide agent risk with it and is readily resorbed by the body, that is to say smaller dosage amounts are required and good transport through tissue membranes is achieved.